雌激素受体α（ERα）作为核受体超家族成员通常以配体依赖方式介导基因转录，并招募一系列辅调节因子参与调控其转录活性。ERα及其辅调节因子在乳腺癌进程中扮演着重要角色。申请人早期利用果蝇模型筛选出BAP18作为一种新的H3K4me3 reader调控基因转录。然而BAP18的转录调控功能是否具有时空特异性，它本身的转录是如何被诱导和调控，BAP18如何影响乳腺癌进程等仍有待深入研究。本项目前期研究发现BAP18上调ERα介导基因转录；同时其本身转录受ERα-E2调节，提示BAP18可能与ERα形成正反馈调控回路。此外，敲低BAP18影响了乳腺癌细胞生长及细胞周期进程。本项目试图阐明BAP18调控ERα转录活性的表观遗传学新机制，揭示其调控转录的时空特异性，明确BAP18是ERα新的下游调控基因，解析BAP18在乳腺癌中的作用及其与ERα的依存关联，为乳腺癌早期诊断和治疗提供实验依据和新靶点。

Estrogen receptor α (ERα) is a member of steroid hormone receptor superfamily. In the presence of ligand, ERα exerts its biological function by regulating transcription of target genes. Co-regulators are recruited for regulating these processes. ERα and its co-regulators play essential roles in breast cancer progression and endocrine therapy resistance. Thus, identification of ERα co-regulators as a potential therapy target for breast cancer is important. However, whether BAP18 possesses a temporal and spatial specificity to regulate transcription? How is BAP18 itself transcription induced and regulated? How does BAP18 influence the progression of breast cancer? These questions are still needed to be clarified. In the previous study, a histone H3K4me3 reader, BAP18 has been identified to be involved in transcription regulation. Further study indicates that depletion of BAP18 influences H3K4me3 and H4Ac modification levels at the estrogen-response elements of ERα target genes, and BAP18 may interact with WDR5, ASH2L, and DYP30 to modulate ERα action. Importantly, our data have demonstrated that ERα-E2 signaling is able to induce BAP18 itself transcription, suggesting that BAP18 could form a positive feedback regulation with ERα in breast cancer. Furthermore, our results have shown that BAP18 depletion inhibits ERα-positive breast cancer cell growth, and influences cell cycle progress. The expression of BAP18 is positive correlated with that of ERα in breast cancer samples. All above results indicate that BAP18 may participate in modulation of histone modification through the recruitment of other important histone modification enzymes to promote ERα-mediated transcriptional activity, and play a crucial role in breast cancer progression. Using ChIP, Co-IP, real time PCR, RNA-seq, and ChIP-seq experiments, the aim of our project is to analyze the new epigenetic mechanism underlying modulation function of BAP18 on ERα-mediated transactivation to bring insight into its temporal and spatial specificity. Moreover, EMSA, luciferase assay, and ChIP assay will be performed to clarify that BAP18 acts as a new target gene induced by ERα. We will further study the role of BAP18 in breast cancer growth, tamoxifen resistance, and tumor invasion and metastasis to analyze whether the funtion of BAP18 in breast cancer is related to ERα. In the future, we will try to supply experimental evidences and new targets for the early detection and therapy of breast cancer.